This program project grant renewal application has two major research foci: (1) studies on central nervous and cardiovascular changes in noradrenergic transmission that accompany senescence and 2) cholinergic mechanisms that may underlie age-related declines in cognitive function. One basic objective, historically the major focus during the previous six years of the program, continues to be the study of the mechanism of age-related changes in the pharmacological properties of the central nervous and cardiovascular systems. We will study age-related changes in drug responsiveness in both experimental animal models and in man. The molecular mechanisms for such changes, in term of receptors, of second messenger molecules and of the regulation of presynaptic function will be pursued biochemically using both animal and human tissues. Physiological correlates will be examined using techniques of electrical recording, in vivo chronoamperometry, and electrical stimulation. Morphological correlates in both neuronal and non-neuronal elements will be evaluated. Tissue transplantation will be utilized to determined the intrinsic versus extrinsic nature of any age-related central nervous changes. The major hypothesis to be pursued is that per-and/or postsynaptic changes in CNS synaptic circuitry or in peripheral autonomic neuroeffector mechanism will underlie many of the alterations in adrenergic drug responsivity seen with aging. Our second research focus, studies on central nervous synaptic changes which may underlie cognitive dysfunction, represents the major new research initiative if the program. Major efforts in this program will be devoted to examination of aged-related changes in cholinergic circuitry, effects of neuronotrophic factors and transplants, cellular models of memory such as long-term potentiation (LTP) and putative molecular mechanisms of LTP such as phosphorylation of synaptic proteins. Again in admixture of behavioral, electrophysiological, electrochemical and biochemical approaches will be utilized. Our efforts will cover a broad spectrum ranging from molecular genetic approaches to studies of neuronotrophic agents, to participation on a clinical trial using NGF infusion intracerebrally into patients with Alzheimers Disease.